The uncontrolled proliferation and spreading of abnormal cells throughout the body is the foundation of cancer. More than 200 distinct forms of cancer exist, and they are all called after the organ or tissue from which they first arise. Breast cancer, prostate cancer, skin cancer, lung cancer, and colon cancer are a few prevalent forms (Adams et al., 2000; Addisu et al., 2024; Al Kawas et al., 2022; Skallevold et al., 2021).

Early diagnosis and identification can help in treating the cancer more effectively. Salivary fluid biomarkers are one of the body fluids employed in this procedure, along with physical examinations, laboratory testing, imaging procedures (such as MRIs, CT scans, and X-rays), biopsies, and other methods. The salivary glands secrete saliva, a slightly acidic oral fluid with a pH of 6–7. The saliva composition is 94%–99% water, 0.3% proteins, various cellular components, and 0.2% organic and inorganic substances (Tiwari, 2011; Kaczor-Urbanowicz et al., 2019). Saliva also contains omics molecular biomarkers, which are found in blood and urine and can be used to identify and track several cancer types, including pancreatic, gastric, lung, and oral cancer (Kaczor-Urbanowicz et al., 2019; Buzalaf et al., 2012; Vukosavljevic et al., 2014).

The main three salivary glands—the parotid, submandibular, and sublingual including the small salivary glands make up human saliva, a complex and dynamic body fluid (Yoshizawa et al., 2013). Saliva carries many important biological functions, including defense, food digestion, lubricating tissues, and clearing the mouth of food particles, and bacteria. Furthermore, saliva is the primary biological factor preventing tooth demineralization. Saliva serves as a buffer, diluting and neutralizing the acids from meals and the bacterial metabolism of the biofilm (Ahsan, 2019). The teeth’s protective layer against mineral loss, the acquired enamel pellicle, is likewise influenced by saliva (Yoshizawa et al., 2013; Buzalaf et al., 2020). Saliva’s excessively high hydroxyapatite content inhibits demineralization and encourages remineralization of dental tissues when the pH of the oral environment changes (Ahsan, 2019).

The National Institutes of Health (NIH) (Podzimek et al., 2016) defines a biomarker as a trait that can be consistently examined and assessed to serve as an indication of pathogenic processes, normal biological processes, or pharmacological responses to therapy. The identification and measurement of biomarkers found in body fluids is crucial for tracking the state of hereditary susceptibilities, pathological illnesses, and reactions to treatments and environmental factors in both clinical practice and research (Ahsan, 2019; Kaczor-Urbanowicz et al., 2017).

Saliva has been identified as a crucial body fluid for the identification of molecules that may serve as biomarkers for a range of systemic pathologies, including neurological, vascular, endocrine, cancer, and psychiatric disorders, as well as oral diseases like periodontitis and caries (Dawes and Wong, 2019; Helmerhorst and Oppenheim, 2007). In this context, it is important to emphasize that saliva and the acquired enamel pellicle are useful tools for biomarker identification. It contains around 3000 proteins, approximately half of which are similarly found in blood (Ahsan, 2019). In addition, when markers are present in both saliva and blood, they are usually found in higher concentrations in the latter, and patients prefer to donate saliva since it may be taken easily, painlessly, and without intrusive procedures. Saliva collection requires fewer steps and discomfort than urine or blood collection, which increases patient involvement—whether the patient is a child, an adult person, or someone with a disability (Gabryel-Porowska et al., 2014; Kaczor-Urbanowicz et al., 2017).

Saliva collection and processing also have low biological risk and low operating costs because they do not require workers or specialized equipment (Schulz et al., 2013). Saliva from each gland separately or may be needed, depending on the purpose of the investigation. However, for biomarker analysis, whole saliva is typically the best option. Sputum or spit, suction, and drainage are the methods most used to gather total saliva. Saliva can be collected in its entirety either while at rest (unstimulated saliva) or upon chewing, taste, or the application of pharmacological stimuli. Excessive caution should be used when collecting stimulated saliva since continuous stimulation of salivary flow may lead to insufficient glycoprotein glycosylation. Specialized tools, like the Lashley Cup, are used to do this (Ahsan, 2019). Preserving biomarkers until analysis is possible is another matter that needs to be addressed. Salivary proteins appear to degrade more quickly than serum proteins (Siqueira and Dawes, 2011; Goldoni et al., 2021). It is necessary to gather and preserve saliva to preserve the sample’s protein content. When assessing the stability of salivary biomarkers, proteolysis and incomplete protein glycosylation processes are important aspects to consider (Holmberg and Hoffman, 2014; Page et al., 2021).

Saliva contains some biomarkers, like proteins, DNA, RNA, and microRNAs, which can reveal important information about the existence and spread of cancer (Ahsan, 2019). These indicators may indicate irregular protein expression, genetic changes, or the release of chemicals particular to tumors into the saliva. Early cancer detection—even before symptoms appear—is made feasible by the analysis of salivary biomarkers (Ahsan, 2019; Sembler-Møller et al., 2020). Analyzing salivary biomarkers in-depth has enormous potential to improve cancer treatment. It makes it possible to create precise and sensitive diagnostic tools that enable early identification and action. Furthermore, salivary biomarkers can be utilized to track the course of a disease and the response to treatment (Ahsan, 2019), informing treatment choices and enhancing patient care. Particularly for those with a high risk of acquiring specific cancers, saliva collection is particularly appropriate for routine screening and monitoring due to its non-invasive nature.

The purpose of this review is to evaluate the potential mechanisms by which distant tumors influence changes in salivary biomarker profiles and cancer therapy, as well as to describe recent advancements in salivary biomarkers utilized for systemic cancer diagnosis. This will help raise awareness of the difficulties among researchers and clinicians with the hope that collaborative efforts in this field will lead to the generation of good solutions more swiftly.

Dataset: The literature query was analyzed using PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analyses) guidelines (Gug et al., 2019).

Literature databases and search scheme: Searches were conducted using a combination of keywords, including salivary biomarkers, cancer, non-invasive cancer screening, therapeutic efficacy, and innovations in analytical techniques. The set of databases included Science Direct, Scopus, and PubMed. Records were identified for full-text scientific articles, published only in chemistry, medicine, toxicology or analytical journals, between 2020 and 2024. We also manually searched the bibliography of selected articles, reviews, meta-analyses, and practical tips. The 77 articles selected have been mutually agreed upon by the authors.

The results of the systematic review are based on a comprehensive literature search conducted across PubMed, Scopus, and Science Direct. The inclusion process followed PRISMA guidelines to ensure transparency and reproducibility. The following flow diagram summarizes the study selection process, from identification to final inclusion (Figures 1, 2).

Salivary biomarkers have emerged as a promising tool in the field of cancer management, offering a non-invasive and accessible approach to tackling this complex disease. These biomarkers, which can be derived from various molecules present in saliva, including DNA, RNA, proteins, and metabolites, have the potential to revolutionize how we detect, diagnose, monitor, and even predict the prognosis of various types of cancer.

One of the most exciting applications of salivary biomarkers is in the sphere of early cancer detection. Numerous studies have demonstrated the ability of these biomarkers to identify the presence of cancer even before clinical symptoms become apparent (Pereira et al., 2020; Bel’skaya and Dyachenko, 2024). This early detection capability is crucial, as it can lead to timely intervention and significantly improve treatment outcomes for patients. Moreover, salivary biomarkers have shown promise in differentiating between cancerous and benign lesions, aiding in accurate diagnosis, and guiding appropriate treatment strategies (Chakraborty et al., 2019; Sancesario and Bernardini, 2019).

Beyond diagnosis, salivary biomarkers have also proved valuable in monitoring the effectiveness of cancer treatments. By tracking changes in the levels of specific biomarkers during and after treatment, clinicians can gain valuable insights into the patient’s response to therapy and make informed decisions about adjusting the course of treatment as needed (Hartmann and Ledur Kist, 2018).

Perhaps most intriguing is the potential of salivary biomarkers to predict disease prognosis and the likelihood of cancer recurrence. Certain biomarker profiles have been associated with more aggressive disease trajectories or higher risks of relapse, allowing for the development of personalized treatment plans that optimize patient outcomes (Spielmann and Wong, 2011).

As the field of salivary biomarker research continues to evolve, we can expect to see even more advancements in the clinical application of these non-invasive tools. With their ability to provide valuable insights at various stages of cancer management, salivary biomarkers hold the promise of transforming the way we approach this complex and challenging disease (Langie et al., 2016).

The detection and diagnosis of cancer remains challenging, especially in its early stages when symptoms are often nonspecific. The development of easy, precise, and non-invasive cancer screening, diagnosis, and management techniques requires urgent attention. Because biofluid-based detection uses molecular biomarkers and is non-invasive, it has the potential to identify diseases early in high-risk patients.

Recent developments in high-throughput omics analysis have played a major role in the identification of biofluid-based cancer-associated biomarkers. Nevertheless, despite great efforts, only a small number of biomarkers have been included into standard clinical practice, and even fewer have received approval for diagnosis or screening of the entire population.

Salivary biomarkers are becoming more widely acknowledged for their ability to track the development and response to therapy of cancer in addition to detecting it. For example, tumour regression or resistance in oral squamous cell carcinoma has been associated with dynamic variations in IL-8 or TNF-α levels throughout therapy. Similar to this, changes in miRNA profiles, including those of miR-31 and miR-200a, before and after chemotherapy can show how well a treatment is working for lung and breast cancer. It has been suggested that monitoring polyamine levels and particular exosomal RNA fragments can be used to detect minimal residual disease in gastric and pancreatic malignancies. These long-term biomarker evaluations offer a non-invasive and economical method of managing cancer in a personalized manner, allowing for prompt therapy modifications and enhancing prognosis. Challenges such as the heterogeneity of cancer pathology and technical issues with omics technologies persist, underscoring the need for further research and development (Adams et al., 2000; Addisu et al., 2024; Al Kawas et al., 2022).

The research of salivary biomarkers could undergo an enormous shift as a result of developments in nanotechnology and artificial intelligence. Point-of-care diagnostic devices that assess multi-analyte saliva profiles for rapid chairside diagnosis are being developed with machine learning algorithms. The miniaturization of lab-on-a-chip technologies, which process and analyze minute salivary samples in real-time, has made distributed cancer screening viable even in low-resource contexts. Multinational consortiums, such as the Salivaomics Knowledge Base, are also attempting to standardize the processes involved in the identification and validation of biomarkers. As these technologies develop, salivary diagnostics might soon be included into routine cancer operations, enabling earlier detection, more accurate monitoring, and better patient outcomes.